Dual biologics for severe asthma and atopic dermatitis: Synopsis of two cases and literature review

Abstract The efficacy and safety of the combination of biologic therapies remain unclear with an ineffective and insufficient single biologic for managing asthma. Herein, we report two cases using dual biologics for severe asthma and atopic dermatitis. A 52‐year‐old male patient who received dupilumab and mepolizumab, benralizumab, or tezepelumab, followed by bronchial thermoplasty, and a 41‐year‐old male patient who received dupilumab and omalizumab, both experienced improved asthma and atopic dermatitis. To date, 38 cases are using dual biologics for severe asthma. The success rate was 84%, with no major adverse effects. We report the first case of severe asthma receiving dual biologics with tezepelumab and furthermore bronchial thermoplasty, and comprehensive literature review on dual biologics. Dual biologics may be an effective treatment method for severe asthma, requiring further investigation.


INTRODUCTION
2][3][4][5] These biologics are widely used for treating not only severe asthma but also other allergic disorders, including chronic spontaneous urticaria, atopic dermatitis, and chronic rhinosinusitis. 6,7Switching to an alternative biologic is recommended rather than resorting to combination therapy when a single biologic is ineffective or insufficient for managing asthma. 8However, modifying only one pathway for asthma pathophysiology might be insufficient, and a clinical situation sometimes works well with a combination of biologic therapies.
][11][12][13][14][15][16] Notably, one case series presented a favourable response in 11 out of 15 (73%) cases that received dual biologic therapy. 16erein, we report two cases receiving dual biologics.Dupilumab is a good candidate for patients with severe asthma and atopic dermatitis; however, when dupilumab fails to effectively manage asthma and an alternative biologic lacks strength for atopic dermatitis, the potential of dual biologics, inclusive of dupilumab, becomes an enticing strategy.We also provide a comprehensive literature review on the combination of biologic therapies for severe asthma, thereby augmenting the existing evidence surrounding dual biologic interventions.

CASE REPORT Case 1
A 52-year-old male patient was referred to our hospital for severe asthma treatment.He had a history of childhood asthma, chronic spontaneous urticaria, and atopic dermatitis.He had never smoked and had no drug or food allergies.The following laboratory tests were evaluated: white blood cell count of 5700/mm 3 with 4.9% eosinophils, total serum IgE of 1176 IU/mL, and specific IgE levels for house dust of 9.73 UA/mL.Omalizumab administration was initiated, which resolved asthma.He had been prescribed oral corticosteroids; however, tapering had been unsuccessful.Four months later, omalizumab was replaced with dupilumab, expecting additive improvement in atopic dermatitis.Unfortunately, this change triggered the onset and progression of conjunctivitis.Therefore, dupilumab was replaced with mepolizumab.This adjustment worsened dermatitis.Consequently, dupilumab was reintroduced with continuing mepolizumab.This combination effectively managed atopic dermatitis without deteriorating conjunctivitis.Nonetheless, asthma management remained suboptimal; therefore, mepolizumab was replaced with benralizumab.Regrettably, this alteration failed to ameliorate asthma.Therefore, benralizumab was replaced with tezepelumab, resulting in a 5-month period of partially improved asthma management.However, a gradual elevation in eosinophil count and a loss of asthma management occurred.Consequently, tezepelumab was again replaced with benralizumab, and the patient underwent bronchial thermoplasty.At present, he continues benralizumab and dupilumab treatment (Figure 1).The use of dual biologics demonstrated no adverse effect associations.

Case 2
A 41-year-old male patient was referred to our hospital for severe asthma treatment.He had a history of childhood asthma and atopic dermatitis.He had a history of 2 pack-year smoke and had no drug or food allergies.The following laboratory tests were evaluated: white blood cell count of 11,200/mm 3 with 4.2% eosinophils, total serum IgE of 9290 IU/mL, and specific IgE levels for house dust of 11.40 UA/mL.Omalizumab was initiated, which subsequently resolved asthma.However, atopic dermatitis remained uncontrolled.Six years later, dupilumab was initiated to manage atopic dermatitis while continuing omalizumab.This dual biologic approach demonstrated significant improvement in atopic dermatitis, prompting the discontinuation of omalizumab.However, omalizumab cessation coincided with asthma progression, necessitating the initiation of regular oral corticosteroid therapy.Therefore, omalizumab was reintroduced with continuing dupilumab.This combined regimen showed successful asthma management, making his current maintenance of omalizumab and dupilumab (Figure 2).The use of dual biologics demonstrated no adverse effect associations.

DISCUSSION
Herein, we describe two cases of severe asthma with atopic dermatitis that were successfully managed through the initiation of dual biologic therapies.Dual biologics, particularly incorporating dupilumab, may be a good candidate for patients with both severe asthma and atopic dermatitis.Notably, this is the first case of severe asthma receiving dual biologics including tezepelumab and furthermore bronchial thermoplasty.In addition, we firstly present a comprehensive literature review on dual biologics to date, making a significant contribution to the existing knowledge base.
The important point of our investigation includes the safe and efficacious use of these dual biologic regimens.Dupilumab targets IL-4/IL-13 and improves both severe asthma and atopic dermatitis. 4,6However, patients with atopic dermatitis tended to suffer from conjunctivitis after dupilumab administration. 17The use of mepolizumab in addition to dupilumab, which targets both IL-4/13 and IL-5 pathways, may improve atopic dermatitis and conjunctivitis, all while managing severe asthma in case 1. Tezepelumab, which targets TSLP, appears as a potential therapeutic option for severe asthma, irrespective of type 2 markers. 5argeting both IL-4/13 and TSLP pathways could have a synergetic effect; however, the effect may be similar to other dual biologics.The use of omalizumab in addition to dupilumab, which targets both IL-4/13 and IgE pathways, may improve both atopic dermatitis and severe asthma in case 2. Dupilumab, in fact, reduces total IgE levels and impacts the IgE pathway. 4On the other hand, omalizumab plays a different role in the pathophysiology of asthma.It increases circulating regulatory T cells, reduces circulating free IgE levels and decreases the expression of type 1 Fcε receptors in dendritic cells, mast cells, basophils, and eosinophils.These mechanisms may account for the additive benefit observed when omalizumab was combined with dupilumab in case 2. 18 These two cases demonstrated the advantages of dual
biologics in patients who remain unmanaged by single biologic treatments, especially when complicated by comorbid conditions with evidence of other biologics.Additionally, these two cases indicated the benefit of concurrently targeting IL-4/13 and other pivotal pathways such as IL-5, TSLP, or IgE.
In case 1, bronchial thermoplasty was introduced after the initiation of dual biologics, resulting in improved asthma control.Bronchial thermoplasty has demonstrated a sustained reduction in severe asthma exacerbations over a period of 10 years. 19This long-term effect may hold promise even for patients receiving dual biologic therapy.To our knowledge, this is the first case in which bronchial thermoplasty was combined with dual biologics.Consequently, it is imperative to closely monitor the safety as well as efficacy of incorporation of bronchial thermoplasty in the future.
][11][12][13][14][15][16] These cases were aged 49 ± 16 years, consisting of approximately one-third male.The effective rate of dual biologics for asthma was 21/25 (84%) while acknowledging potential publication bias.Comorbidities included only asthma in 15 (39%), chronic rhinosinusitis in 9 (24%), atopic dermatitis in 6 (16%), eosinophilic granulomatosis with polyangiitis in 5 (13%), chronic spontaneous urticaria in 4 (11%), allergic rhinitis in 4 (11%), and allergic bronchopulmonary aspergillosis in 3 (8%) patients.The most used combination was omalizumab and mepolizumab (42%).Dual biologics were administered due to asthma (58%), comorbidities (34%), or both (8%).Dual biologics are avoided because of concerns of serious infections in rheumatoid arthritis or inflammatory bowel diseases in the context of adverse effects. 20,21However, our findings emphasized the safety of dual biologic administration for asthma management, in all the cases, including ours, that experience no serious adverse effects such as anaphylaxis, immune dysfunctions, or infections.Therefore, dual biologics may be considered for promising therapeutic option when patients have multiple potential therapeutic targets and a situation where a single biologic is inadequate.However, this field warrants further prospective evidence.Clinical trials for dual biologics should be performed for patients with severe asthma in whom a single biologic is insufficient for management, safety followup should be included in registries, and a longer follow-up should be performed.As the strategy of the use of dual biologics, we should initially attempt to switch to another biologic, and dual biologics are considered when each biologic responds partially but insufficiently to control the situation.
Cost should be also considered.Adding another biologic increases costs; however, this investment may be offset by a reduction in repeated emergency department visits or hospitalizations and productivity improvement. 22Therefore, dual biologics would be acceptable in terms of costs when careful selection is performed.
In conclusion, dual biologics, with dupilumab and other biologics, including tezepelumab, may be an effective therapeutic strategy for patients with both severe asthma and atopic dermatitis.Future prospective study is required to investigate the efficacy and safety of the combination of biologics because only case reports or case series have been reported.

F I G U R E 1
Clinical course in case 1. Black figure size represents the degree of symptoms of each situation.Red arrows represent the occurrence of short burst, while blue arrow represents the performance of BT.FeNO, fractional exhaled nitric oxide; FEV 1 , forced expiratory volume in 1 s.ACT, asthma control test; BT, bronchial thermoplasty; ICS, inhaled corticosteroid; IGA, investigator global assessment; IgE, immunoglobulin E; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; PSL, prednisolone.

F I G U R E 2
Clinical course in case 2. Black figure size represents the degree of symptoms of each situation.Red arrows represent the occurrence of short burst.FeNO, fractional exhaled nitric oxide; FEV 1 , forced expiratory volume in 1 s.ACT, asthma control test; ICS, inhaled corticosteroid; IGA, investigator global assessment; IgE, immunoglobulin E; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid.T A B L E 1Previous reports of dual biologics for asthma.